Renal function after liver transplantation : Real-world experience with basiliximab induction and delayed reduced-dose tacrolimus

Background: Routine use of delayed reduced-dose calcineurin-inhibitor treatment with induction immunosuppression in liver transplantation to minimize post-operative kidney injury is still scarce. im: To evaluate real-world experience of basiliximab induction with delayed reduced-dose tacrolimus. Methods: In a retrospective cohort study, kidney function was evaluated pre-and postoperatively by mea-sured glomerular filtration rate (mGFR). Adult patients undergoing liver transplantation between 20 0 0 and 2017 were divided into a conventional treatment group (immediate-introduction of tacrolimus, tar-get trough levels 10-15 ng/mL, and corticosteroids, n = 203) and a revised treatment group (basiliximab induction, reduced-dose tacrolimus, target through levels 5-8 ng/mL, delayed until day three, and my-cophenolate mofetil 20 0 0 mg/day, n = 343). Results: Mean mGFR was similar between groups at wait-listing (85.3 vs 84.1 ml/min/1.73m2, p = 0.60), but higher in the revised treatment group at 3 (56.8 vs 63.4 ml/min/1.73m2, p = 0.004) and 12 months post-transplant (60.9 vs 69.7 ml/min/1.73m2, p < 0.001); this difference remained after correcting for mul-tiple confounders and was independent of pre-transplant mGFR. In the revised treatment group, biopsy proven acute rejection rate was lower (38% vs. 21%, p < 0.001), and graft-survival better ( p = 0.01). Conclusion: Basiliximab induction with delayed reduced-dose tacrolimus is associated with less kidney injury when compared to standard-dose tacrolimus, without increased risk of rejection, graft loss or death. (c) 2021 The Authors. Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l.Peer reviewe

Exploring gastrointestinal variables affecting drug and formulation behavior: methodologies, challenges and opportunities

Various gastrointestinal (GI) factors affect drug and formulation behavior after oral administration, including GI transfer, motility, pH and GI fluid volume and composition. An in-depth understanding of these physiological and anatomical variables is critical for a continued progress in oral drug development. In this review, different methodologies (invasive versus non-invasive) to explore the impact of physiological variables on formulation behavior in the human GI tract are presented, revealing their strengths and limitations. The techniques mentioned allow for an improved understanding of the role of following GI variables: gastric emptying (magnetic resonance imaging (MRI), scintigraphy, acetaminophen absorption technique, ultrasonography, breath test, intraluminal sampling and telemetry), motility (MRI, small intestinal/colonic manometry and telemetry), GI volume changes (MRI and ultrasonography), temperature (telemetry) and intraluminal pH (intraluminal sampling and telemetry)

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Duodenal motility in humans. Studies based on manometry with a high resolution technique

Late phase III of the interdigestive state is characterized by a retroperistaltic sequence in the descending duodenum followed by increases of antral pH. In this thesis the spatial organization of duodenal propagating pressure waves was further studied in the interdigestive state and postprandially. Furthermore, the relationship between interdigestive duodenal motility and luminal transport of duodenal contents and the potential effects of benzodiazepines (midazolam) on small bowel motility were studied. Antroduodenal manometry with a high temporospatial resolution technique was performed in healthy subjects. The intraluminal transport of a duodenal marker and a bile marker was studied by scintigraphy. In the most juxtapyloric duodenum the pressure waves were mainly retrograde in both early and late phase III (medians, 66 and 83%, respectively) and postprandially (40-50%). The duodenal propagating pressure waves of phase III were divergent along the entire duodenum with a proximal retrograde and a distal antegrade propagation direction from the start site of the pressure waves. The start site of the contractions moved gradually distal in the duodenum. There were no pyloric contractions during the retroperistaltic sequence of late duodenal phase III. The retroperistaltic activity fronts were always (100%) followed by retropulsion of duodenal marker to the stomach. A clear-cut reflux of bile marker was seen in only 17% of the activity fronts. Instead, the bile marker contents increased abruptly in the gallbladder during phase III. The incidence rate of duodenogastric reflux was highest in phase III compared with phase II (p&lt;0.008). Midazolam affected only five out of 28 small bowel motility variables, e. g., shortening of MMC-duration, but duodenal phase III retroperistalsis was preserved.Conclusions: The duodenal contractions of phase III are divergent with retropropagation in the proximal part. The retroperistalsis is selectively propelling alkaline refluxate of duodenal origin to the stomach in late duodenal phase III. This physiologic duodenogastric reflux is aided by a non-contracting pylorus. Divergent contractions are also common postprandially in the juxtapyloric duodenum, tentatively contributing to gastric emptying regulation. Benzodiazepines, as studied by midazolam, have few motility effects and do not affect the phase III-related retroperistalsis

No need to discontinue hepatitis C virus therapy at the time of liver transplantation.

ObjectivesDirect antiviral agents (DAA) has dramatically improved the therapy outcome of hepatitis C-virus (HCV) infection, both on the waiting-list and post liver transplantation (LT). DAA are generally well-tolerated in patients with mild to moderate liver and kidney failure, but some DAAs are contraindicated in patients with severe dysfunction of these organs. Today there are few studies of peri-LT DAA use and treatment is commonly discontinued at the time of LT. We report here our experience of DAA therapy given continuously in the perioperative LT period in a real-life setting in Sweden.MaterialIn total 10 patients with HCV-cirrhosis, with or without hepatocellular carcinoma, and a median age of 60.5 years (range, 52-65) were treated with DAAs on the waiting list for LT, and continued in the early postoperative period without any interruption, on the basis of not having reached a full treatment course at the time of LT. Sofosbuvir and a NS5A inhibitor with or without ribavirin, or sofosbuvir and ribavirin only, were given. The distribution of genotypes was genotype 1 and 3, in 4 and 6 patients, respectively. Six of the 10 patients had previously been treated with IFN-based therapy.ResultsThere were no adverse events leading to premature DAA discontinuation. All recipients achieved a sustained viral response 12 weeks after end-of-treatment (SVR12). At the time of LT the median MELD-score was 16.5 (range 7-21), CTP-score 9.0 (range 5-10), creatinine 82.5 μmol/L (range 56-135, reference 60-105), bilirubin 33 μmol/L (range 16-79, reference 5-25) and PK-INR 1.5 (range 1.1-1.8). The median duration of DAA therapy was 60 days (range 18-132) pre-LT, 54 days post-LT (range 8-111 days) and in total 15.5 weeks (range 12-30 weeks).ConclusionInterferon-free DAA therapy of HCV-infection given in the immediate pre- and post-operative LT period is safe, well-tolerated and yields high SVR rates

Pre-transplant renal impairment predicts posttransplant cardiac events in patients with liver cirrhosis.

To access publisher's full text version of this article click on the hyperlink at the bottom of the pageCardiovascular disease and renal impairment are common in cirrhotic transplant candidates. We aimed to investigate potential association between pretransplant renal function impairment and cardiac events after liver transplantation.Adult cirrhotic patients undergoing first-time liver transplantation between 1999 and 2007 in a single institution with available glomerular filtration rate (GFR), assessed by Cr-EDTA clearance at pre-transplant evaluation, were retrospectively enrolled (n=202). Impaired renal function was defined as GFR less than 60 mL/min/1.73 sqm. Pretransplant QT-time corrected by heart rate (QTc) and left-ventricular dysfunction was also registered. Mortality and cardiac events were analyzed, until death or last follow-up (end 2009).Renal impairment was present in 24% (48/202). Cardiac events occurred in 28% (56/202) after transplantation, mean follow-up time of 3.8 years (2.2). Events were more common in patients with renal impairment compared with those without (48% versus 21%, P0.05). A pretransplant score comprising renal impairment, prolonged QTc interval, and age older than 52 was developed for prediction of 3- and 12-month cardiac events (c-statistic 0.73 and 0.75, respectively).Pretransplant renal impairment is a predictor of cardiac event after liver transplantation together with prolonged QTc interval.Medical research council of Vastra Gotaland in Sweden/ALF-2210

Osteoporosis in cirrhotics before and after liver transplantation : relation with malnutrition and inflammatory status

Background: Liver cirrhosis is associated with osteoporosis and liver transplantation (LT) with increased bone loss. This study aimed to in LT candidates investigate the potential relation between bone mineral density (BMD) and BMD loss in those who undergo LT, with malnutrition, systemic inflammation, and hormonal status. Methods: We included 102 consecutively recruited cirrhotic LT candidates between May 2004 and April 2007. BMD was assessed by means of dual energy X-ray absorptiometry (DXA). Malnutrition was defined by means of anthropometry and assessment of recent weight loss. In 75/102 patients, serum-thyroid stimulating hormone (TSH), free triiodthyronine (T3) and free thyroxine (T4) and growth hormone (GH), cortisol, free testosterone, dehydroepiandrosterone sulfate, estradiol, interleukin-6, and tumor necrosis factor (TNF)-α was assessed. Overall 57/102 patients received a LT and 47/102 were followed for one year post-LT. At follow-up, nutritional status and BMD were assessed in all patients (n = 47) while 34/47 had available blood samples for analysis. Results: Forty (40%) LT- candidates had osteopenia or osteoporosis and 34 (38%) were malnourished. Malnutrition was associated with osteopenia/osteoporosis (odds ratio: 3.5, 95% CI 1.4, 9.9). Hip BMD Z-score decreased −0.25 (95% CI −0.41, −0.09) from baseline to one year post-LT. High baseline TNF-α correlated with a more marked decline in BMD (Partial correlation (r) = −0.47, p <.05) as did high baseline cortisol levels (r = −0.49, p <.05). Conclusion: Malnutrition in liver cirrhosis seems to be associated with osteopenia/osteoporosis, and systemic inflammation (higher TNF-α) and systemic stress (higher cortisol) to bone loss in patients who undergo LT

Impact of cardiac dysfunction on health-related quality of life in cirrhotic liver transplant candidates.

To access publisher's full text version of this article click on the hyperlink at the bottom of the pageCardiac dysfunction, in particular left ventricular diastolic dysfunction, is common in cirrhosis. We aimed to investigate the impact of cardiac dysfunction on health-related quality of life (QoL) in liver cirrhosis.A total of 88 cirrhotic liver transplant candidates with an available echocardiogram and ECG completed the Short form-36 (SF-36) and Fatigue Impact Scale. In a subgroup of 61 patients, levels of cardiac biomarkers, in particular serum N-terminal pro-brain natriuretic peptide, adiponectin, and high-sensitive troponin T, were also measured.Although left ventricular systolic diameter was related to a lower SF-36 physical component summary, neither left ventricular diastolic dysfunction nor any other echocardiographic feature was found to be associated with any other SF-36 or Fatigue Impact Scale domain (P>0.05 for all). On linear regression analysis after adjustment for confounders, a prolonged QTc interval was found to be related to a lower SF-36 mental component summary score (β=-9.7, P=0.009) and increased physical fatigue (β=10.5, P=0.004). Neither serum N-terminal pro-brain natriuretic peptide, high-sensitivity troponin T, nor adiponectin levels were found to be related to QoL (P>0.05 for all). Serum adiponectin levels did not differ among patients with versus those without echocardiographic cardiac alterations (P>0.05 for all).A prolonged QTc interval, but not any echocardiographic abnormalities or cardiac biomarkers, seems to be predictive of QoL in cirrhosis.Medical research council of Vastra Gotaland in Sweden ALF-2210